Concise Total Synthesis of (+)-Aphanorphine

Key words

aphanorphine - total synthesis - alkaloids - tert-butanesulfinimine - cycloaddition - hydrogen-atom transfer

Figure 1 Representative benzomorphan alkaloids

In 1988, an alkaloid named aphanorphine (1) was isolated by Shimizu and Clardy and their co-workers during their studies on the biosynthesis of the neurotoxic alkaloid neosaxitoxin in the freshwater blue-green alga Aphanizomenon flos-aquae.[1] Aphanorphine has a tricyclic benzazepine core and is structurally similar to the natural and synthetic analgesic benzomorphan alkaloids morphine (2), pentazocine (3), and eptazocine (4) (Figure [1]). Its intriguing structure and its potential analgesic biological activity made aphanorphine an attractive target for organic synthesis. Many elegant strategies have been developed to construct the tricyclic benzazepine motif, such as Lewis acid-promoted Friedel–Crafts or tin hydride-mediated radical cyclization of the 2-benzylpyrrolidine intermediate to construct the ring B,[2] transannular enolate or radical cyclization of 3-benzazepine derivatives to form both rings B and C,[3] or intramolecular nucleophilic cyclization of tetralin or dihydronaphthalene substrates to build ring C.[4] Grainger developed a unique approach including a carbamoyl-radical cyclization to close ring C and a late-stage formation of aromatic ring A through an inverse-electron-demand Diels–Alder reaction.[5] Here, we report a concise total synthesis of (+)-aphanorphine (5) based on transition metal-catalyzed cyclization reactions.

The metal-catalyzed hydrogen-atom transfer (MHAT) reaction has emerged as a powerful tool in organic synthesis.[6] [7] As shown in Scheme [1], we envisioned that the ring B and C1 quaternary carbon center of (+)-aphanorphine (5) might be obtained by a radical cyclization initiated by MHAT of the 2-benzylpyrrolidine 6, which, in turn, could be assembled by intermolecular trimethylenemethane (TMM) [3+2]-cycloaddition[8] of the known chiral imine 7 with 2-[(trimethylsilyl)methyl]allyl acetate (8) (Scheme [1]).

Scheme 1 Retrosynthetic analysis of (+)-aphanorphine (5)

Our total synthesis of (+)-aphanorphine (5) commenced with the TMM [3+2]-cycloaddition of 2-[(trimethylsilyl)methyl]allyl acetate (8) with the chiral imine 7 (Scheme [2]),[9] which can be prepared from (4-methoxyphenyl)acetaldehyde (9) and (R)-(+)-tert-butylsulfinamide (10) in 66% yield by a known procedure.[10] Stockman and co-workers previously investigated the TMM [3+2]-cycloadditions of chiral aryl and alkyl tert-butanesulfinimines to yield enantiopure pyrrolidine products.[11] Unfortunately, when we followed Stockman’s method, none of the desired cycloaddition product was detected when 7 and 8 were stirred with Pd(PPh₃)₄ in THF for 18 hours at 25 °C. Instead, the unexpected alkylation product 11 was isolated in 42% yield (Scheme [2a]). We surmised that 11 might be formed by proton transfer from the C5 atom of 7 to the Pd–TMM intermediate 12. The C5 position of 7 is activated by both an electron-withdrawing inductive effect of the imine group and by the conjugate effect of the phenyl group; consequently, instead of the expected cycloaddition of the TMM intermediate 12 with the imine, proton transfer from the C5 atom of 7 to the Pd-TMM intermediate 12 becomes the favored pathway to give methallyl complex 13, which is attacked by the resulting anion 14 to deliver the alkylation product 11.[12]

Scheme 2 Investigation of the [3+2]-cycloaddition

Reports by Trost and co-workers[12a] [c] suggested that increasing the temperature might enhance the nucleophilicity of TMM. Pleasingly, when the reaction mixture was stirred under reflux for 19 hours, our desired cycloaddition products 15a and 15b were obtained in 1:3 dr with a combined yield of 52%, along with the mono- and dialkylation products 11 and 16, respectively, in yields of 9 and 19%. For the synthesis of (+)-aphanorphine (5), the tert-butylsulfinyl group of 15b was removed by treatment with 2 M HCl in MeOH, and the resulting secondary amine was treated with ClCO₂Me in the presence of NEt₃ to give the methyl carbamate 17 in 80% yield over the two steps (Scheme [3]).

Scheme 3 Synthesis of benzylpyrrolidine 17

According to our synthetic plan, the next work was to construct the tricyclic benzazepine core of (+)-aphanorphine (5) through MHAT-based radical cycloaddition. We began our study by evaluating a catalytic system previously used by Shigehisa et al. for the hydroarylation of nonactivated alkenes (Table [1]).[13] Treatment of 17 with 1,1,3,3-tetramethyldisiloxane (TMDSO), N-fluoro-2,4,6-trimethylpyridinium triflate (O1, Figure [2]), and the ethylenediamine-containing salen Co-catalyst C1 in PhCF₃ gave the desired tricyclic benzazepine 18 in only 6% yield (Table [1], entry 1). To our delight, the use of the 1,3-diaminopropane-containing catalyst C2 (Figure [2]) improved the yield to 72% (entry 2). The longer 1,4-butanediamine gave a much lower yield (entry 3). Replacing the tert-butyl group on the 5-position of the aromatic ring of C2 with H, Me, or OMe (C4–C6) led to no conversion (entries 4–6). Further catalyst screening showed that C7 was the best catalyst, affording a 76% yield of the desired product (entries 7 and 8). Next, a series of oxidants including N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (O2), N-fluoropyridinium triflate (O3), N-fluoropyridinium tetrafluoroborate (O4), and (diacetoxyiodo)benzene (O5) were evaluated, but all proved inferior to N-fluoro-2,4,6-trimethylpyridinium triflate (O1) (entries 9–12). Finally, we examined various silanes and we found that poly(methylhydrosiloxane) (PMHS) was superior to TMDSO, PhSiH₃, or Ph(i-PrO)SiH₂,[14] giving an improved yield of 83%[15] (entries 13–15).

Table 1 Optimization of the MHAT-Based Radical Cycloaddition

Entry	Catalysta	Silane	Oxidanta	Yieldb (%)
1	C1	TMDSO	O1	6
2	C2	TMDSO	O1	72
3	C3	TMDSO	O1	12
4	C4	TMDSO	O1	NDc
5	C5	TMDSO	O1	ND
6	C6	TMDSO	O1	ND
7	C7	TMDSO	O1	76
8	C8	TMDSO	O1	13
9	C7	TMDSO	O2	58
10	C7	TMDSO	O3	ND
11	C7	TMDSO	O4	36
12	C7	TMDSO	O5	38
13	C7	PhSiH3	O1	32
14	C7	PMHS	O1	83
15	C7	PhSiH2(O-i-Pr)	O1	27

^a For catalyst and oxidant structures, see Figure [2].

^b Isolated yield.

^c ND = not detected.

Figure 2 Catalyst structures C1–C8 and oxidants O1–O5

With 18 in hand, the remaining transformations of the synthesis were N-methylation and O-demethylation. Reduction of 18 with excess LiAlH₄ afforded (–)-8-O-methylaphanorphine (19) in 88% yield. On following the procedure of Fuchs and Funk,[3a] treatment of 19 with BBr₃ in DCM at a low temperature effected the expected O-demethylation, giving (+)-aphanorphine (5) in 50% yield (Scheme [4]). The physical and spectroscopic data of the synthetic (+)-aphanorphine (5) {[α]_D ²⁵ +20.8 (c 0.4, MeOH)} agreed with those reported previously.[1] [2l]

Scheme 4 Completion of the total synthesis of (+)-aphanorphine (5)

In summary, a concise total synthesis of (+)-aphanorphine (5) was achieved, starting from the known chiral tert-butanesulfinimine 7, in six steps and 11% overall yield. The transition-metal-catalyzed intermolecular TMM [3+2]-cy­cloaddition and a MHAT-based radical cyclization were used in a rapid construction of the tricyclic benzazepine core of the natural product. In addition, methyl carbamate was used as a latent methylamine, avoiding additional steps involving manipulation of N-substituent group, as required in the previous synthesis, thereby improving the overall synthetic efficiency.

• References and Notes

• 1 Gulavita N, Hori A, Shimizu Y, Laszlo P, Clardy J. Tetrahedron Lett. 1988; 29: 4381
• 2a Tamura O, Yanagimachi T, Kobayashi T, Ishibashi H. Org. Lett. 2001; 3: 2427
• 2b Zhai H, Luo S, Ye C, Ma Y. J. Org. Chem. 2003; 68: 8268
• 2c Hu H, Zhai H. Synlett 2003; 2129
• 2d Tamura O, Yanagimachi T, Ishibashi H. Tetrahedron: Asymmetry 2003; 14: 3033
• 2e Bower JF, Szeto P, Gallagher T. Chem. Commun. 2005; 5793
• 2f Bower JF, Szeto P, Gallagher T. Org. Biomol. Chem. 2007; 5: 143
• 2g Ma Z, Zhai H. Synlett 2007; 161
• 2h Ma Z, Hu H, Xiong W, Zhai H. Tetrahedron 2007; 63: 7523
• 2i Yang X, Zhai H, Li Z. Org. Lett. 2008; 10: 2457
• 2j Yang X, Cheng B, Li Z, Zhai H. Synlett 2008; 2821
• 2k Yoshimitsu T, Atsumi C, Iimori E, Nagaoka H, Tanaka T. Tetrahedron Lett. 2008; 49: 4473
• 2l Mai DN, Rosen BR, Wolfe JP. Org. Lett. 2011; 13: 2932
• 2m Medjahdi M, González-Gómez JC, Foubelo F, Yus M. Eur. J. Org. Chem. 2011; 2230
• 2n Pansare SV, Kulkarni KG. RSC Adv. 2013; 3: 19127
• 2o Wang Z, Zheng H, Yang J, Xie X, She X. Adv. Synth. Catal. 2015; 357: 2082
• 2p Peterson LJ, Wolfe JP. Adv. Synth. Catal. 2015; 357: 2339
• 3a Fuchs JR, Funk RL. Org. Lett. 2001; 3: 3923
• 3b Katoh M, Inoue H, Suzuki A, Honda T. Synlett 2005; 2820
• 3c Honda T, Katoh M, Inoue H. Heterocycles 2007; 72: 497
• 3d Donets PA, Goeman JL, Van der Eycken J, Robeyns K, Van Meervelt L, Van der Eycken EV. Eur. J. Org. Chem. 2009; 793
• 4a Takano S, Inomata K, Sato T, Ogasawara K. J. Chem. Soc., Chem. Commun. 1989; 1591
• 4b Takano S, Inomata K, Sato T, Takahashi M, Ogasawara K. J. Chem. Soc., Chem. Commun. 1990; 290
• 4c Honda T, Yamamoto A, Cui Y, Tsubuki M. J. Chem. Soc., Perkin Trans. 1 1992; 531
• 4d Hulme AN, Henry SS, Meyers AI. J. Org. Chem. 1995; 60: 1265
• 4e Fadel A, Arzel P. Tetrahedron: Asymmetry 1995; 6: 893
• 4f Hallinan KO, Honda T. Tetrahedron 1995; 51: 12211
• 4g Meyers AI, Schmidt W, Santiago B. Heterocycles 1995; 40: 525
• 4h Shiotani S, Okada H, Nakamata K, Yamamoto T, Sekino F. Heterocycles 1996; 43: 1031
• 4i Node M, Imazato H, Kurosaki R, Kawano Y, Inoue T, Nishide K, Fuji K. Heterocycles 1996; 42: 811
• 4j Ogasawara K, Shimizu M, Kamikubo T. Heterocycles 1997; 46: 21
• 4k Fadel A, Arzel P. Tetrahedron: Asymmetry 1997; 8: 283
• 4l Fadel A, Arzel P. Tetrahedron: Asymmetry 1997; 8: 371
• 4m Tanaka K, Taniguchi T, Ogasawara K. Tetrahedron Lett. 2001; 42: 1049
• 4n ElAzab AS, Taniguchi T, Ogasawara K. Heterocycles 2002; 56: 39
• 4o Kita Y, Futamura J, Ohba Y, Sawama Y, Ganesh JK, Fujioka H. J. Org. Chem. 2003; 68: 5917
• 4p Taylor SK, Ivanovic M, Simons LJ, Davis MM. Tetrahedron: Asymmetry 2003; 14: 743
• 4q Li M, Zhou P, Roth HF. Synthesis 2007; 55
• 4r Zhu D.-Y, Xu M.-H, Tu Y.-Q, Zhang F.-M, Wang S.-H. Chem. Eur. J. 2015; 21: 15502
• 4s Chiou W.-H, Chen P.-C. J. Org. Chem. 2017; 82: 8213
• 5 Grainger RS, Welsh EJ. Angew. Chem. Int. Ed. 2007; 46: 5377

For reviews about MHAT reaction, see:
• 6a Crossley SW. M, Obradors C, Martinez RM, Shenvi RA. Chem. Rev. 2016; 116: 8912
• 6b Green SA, Crossley SW. M, Matos JL. M, Vásquez-Céspedes S, Shevick SL, Shenvi RA. Acc. Chem. Res. 2018; 51: 2628

For selected applications MHAT reaction in natural product synthesis, see:
• 7a Zhang B, Zheng W, Wang X, Sun D, Li C. Angew. Chem. Int. Ed. 2016; 55: 10435
• 7b Xu G, Elkin M, Tantillo DJ, Newhouse TR, Maimone TJ. Angew. Chem. Int. Ed. 2017; 56: 12498
• 7c Deng H, Cao W, Liu R, Zhang Y, Liu B. Angew. Chem. Int. Ed. 2017; 56: 5849
• 7d Godfrey NA, Schatz DJ, Pronin SV. J. Am. Chem. Soc. 2018; 140: 12770
• 7e Lu Z, Zhang X, Guo Z, Chen Y, Mu T, Li A. J. Am. Chem. Soc. 2018; 140: 9211
• 7f Farney EP, Feng SS, Schäfers F, Reisman SE. J. Am. Chem. Soc. 2018; 140: 1267
• 7g Ji Y, Xin Z, He H, Gao S. J. Am. Chem. Soc. 2019; 141: 16208
• 7h Xu G, Wu J, Li L, Lu Y, Li C. J. Am. Chem. Soc. 2020; 142: 15240
• 7i Chen P, Wang C, Yang R, Xu H, Wu J, Jiang H, Chen K, Ma Z. Angew. Chem. Int. Ed. 2021; 60: 5512
• 8 Yamago S, Nakamura E. Org. React. (Hoboken, NJ, U. S.) 2002; 61: 1

For selected applications of N-tert-butanesulfinimines in natural-product synthesis, see:
• 9a Chuang KV, Navarro R, Reisman SE. Angew. Chem. Int. Ed. 2011; 50: 9447
• 9b Zhao S, Andrade RB. J. Am. Chem. Soc. 2013; 135: 13334
• 9c Chogii I, Njardarson JT. Angew. Chem. Int. Ed. 2015; 54: 13706
• 9d Tian M, Yan M, Baran PS. J. Am. Chem. Soc. 2016; 138: 14234
• 9e Hugelshofer CL, Palani V, Sarpong R. J. Am. Chem. Soc. 2019; 141: 8431
• 9f Li Y, Wang C, Ma Z, Zhang K, Xu X.-T. Org. Lett. 2020; 22: 8589
• 10 Yao Q, Yuan C. J. Org. Chem. 2013; 78: 6962
• 11 Procopiou G, Lewis W, Harbottle G, Stockman RA. Org. Lett. 2013; 15: 2030
• 12a Trost BM, Chan DM. T. J. Am. Chem. Soc. 1979; 101: 6432
• 12b Trost BM, Chan DM. T. J. Am. Chem. Soc. 1983; 105: 2326
• 12c Trost BM, Bringley DA, O’Keefe BM. Org. Lett. 2013; 15: 5630
• 13 Shigehisa H, Ano T, Honma H, Ebisawa K, Hiroya K. Org. Lett. 2016; 18: 3622
• 14 Obradors C, Martinez RM, Shenvi RA. J. Am. Chem. Soc. 2016; 138: 4962
• 15 Methyl (1S,4S)-8-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-1,4-methanobenzo[d]azepine-3-carboxylate (18) A 4 mL vial was charged with sulfinimine 17 (13 mg, 0.05 mmol, 1.0 equiv), catalyst C7 (1.5 mg, 0.0025 mmol, 0.05 equiv), and oxidant O1 (29 mg, 0.1 mmol, 2.0 equiv). PhCF₃ (0.5 mL), previously dried in vacuo for 0.5 h, was then added and the solution was bubbled with N₂ for 10 min. PMHS (22 µL, 0.1 mmol, 2.0 equiv) was added, and the resulting mixture was stirred at 25 °C for 20 h then diluted with EtOAc (2 mL). The solution was washed with H₂O (0.5 mL) and brine (3 × 0.5 mL), then dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by preparative TLC (PE–EtOAc, 5:1) to give a yellow solid: yield; 10.8 mg (83%); mp 89–92 °C; [α]_D ²⁵ +167.3 (c 0.55, CHCl₃). IR (KBr): 3795, 2957, 1701, 1612, 1495, 1453, 1389, 863, 805, 769, 741, 698 cm^–1. Rotamer ¹H NMR (500 MHz, CDCl₃): δ = 7.03 (d, J = 8.4 Hz, 0.5 H), 6.99 (d, J = 8.3 Hz, 0.5 H), 6.85–6.80 (m, 1 H), 6.72 (td, J = 8.3, 2.5 Hz, 1 H), 4.50–4.43 (m, 0.6 H), 4.39–4.32 (m, 0.4 H), 3.82–3.74 (m, 3 H), 3.72–3.66 (m, 1.3 H), 3.63–3.58 (m, 1.7 H), 3.42 (d, J = 10.1 Hz, 0.5 H), 3.36 (d, J = 9.9 Hz, 0.5 H), 3.28 (d, J = 10.0 Hz, 0.5 H), 3.22 (d, J = 9.9 Hz, 0.5 H), 3.18 (d, J = 16.6 Hz, 0.5 H), 3.04 (d, J = 16.6 Hz, 0.5 H), 2.90 (d, J = 16.6 Hz, 1 H), 2.02–1.86 (m, 2 H), 1.57–1.45 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.9, 157.8, 155.1, 154.9, 145.8, 145.7, 130.5, 130.3, 125.7, 125.4, 111.6, 111.4, 109.89, 109.86, 61.6, 61.2, 55.29, 55.27, 54.8, 54.6, 52.2, 52.0, 42.2, 41.7, 41.6, 40.8, 36.4, 35.7, 20.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₀NO₃: 262.1443; found: 262.1437.